Compositions and methods of using nintedanib for improving glaucoma surgery success

ABSTRACT

Compositions and methods of using nintedanib for improving the success rate of glaucoma filtration surgery are disclosed herein. Nintedanib can be used alone or in combination with an anti-metabolite drug in a topical or implant eye formulation.

CLAIM OF PRIORITY

This application is a continuation of International Application NumberPCT/US2017/034792, filed May 26, 2017, which claims the benefit of U.S.Provisional Patent Application Ser. No. 62/344,878, filed on Jun. 2,2016, and U.S. Provisional Patent Application Ser. No. 62/344,870, filedon Jun. 2, 2016, the entire contents of each are hereby incorporated byreference.

TECHNICAL FIELD

The present disclosure relates to ocular compositions comprisingnintedanib and methods of use thereof for improving the success rate ofglaucoma surgery.

BACKGROUND

Glaucoma refers to a group of eye conditions that damage the opticnerve, which is often caused by an abnormally high pressure in the eye.One way to reduce pressure in an eye with glaucoma is to surgicallycreate a drain in the eye. This type of surgery is called a glaucomafiltration surgery, e.g., trabeculectomy. In glaucoma surgery, a pieceof tissue in the drainage angle of the eye is removed, creating anopening. This new opening creates a drain, allowing fluid to drain outof the eye. The eye pressure is reduced because fluid can now drain withrelative ease through the new opening into a reservoir (bleb) underneaththe conjunctiva. The fluid is then absorbed by the body.

As a result of glaucoma filtration surgery, scarring and fibrosis candevelop at the surgical site. The scarring and fibrosis often results ina gradual reduction of filtration and loss of control of intraocularpressure. Excess fibrosis is a key factor leading to scar formation andthe failure of glaucoma filtration surgery. Current treatments forreducing the failure are still inadequate and need improvements.

SUMMARY

In certain aspects, the disclosure provides a method for improving thesuccess rate of glaucoma surgery (e.g., glaucoma filtration surgery) byadministering nintedanib to the eye of a subject in need of suchtreatment. One aspect features a method for adjunctive treatmentassociated with glaucoma filtration surgery in a subject comprisingadministering to a subject in need thereof an effective amount of acomposition comprising nintedanib or a pharmaceutically acceptable saltthereof. The method improves the success rate of glaucoma surgery.Glaucoma surgery includes, for example, the classic trabeculectomymethod, or a minimally invasive glaucoma surgery (MIGS) method selectedfrom the group consisting of Trabectome, gonioscopy-assistedtransluminal trabeculectomy, excimer laser trabeculostomy, andendoscopic cyclophotocoagulation. The glaucoma surgery performed mayalso be a MIGS procedure for implantation of an ocular filtrationdevice, wherein the ocular filtration device is an ocular stent. Forexample, the ocular filtration device may be selected from the groupconsisting of a XEN® gel stent (e.g. subconjunctival stent), an iStent®or, Hydrus™ microstent (Schlemm's canal stents), and CyPass® microstent(e.g. suprachoroidal stent).

In some aspects of the methods disclosed herein, the amount ofnintedanib administered to the subject is effective to extend theduration of lower IOP, increase either the absolute success rate or thequalified success rate for at least 10 days, at least 90 days, at least365 days, at least 750 days, or at least 3650 days following surgery; orwherein the amount of nintedanib administered is effective to prolongbleb survival.

In some aspects, the nintedanib composition is administered in the formof topical ocular formulation (e.g., a topical eye drop) or implant. Insome examples, the nintedanib is in a topical ocular formulationadministered topically to the affected eye. In certain aspect, theconcentration of nintedanib in the formulation is from 0.001% to 10% byweight or by volume the total amount of composition. In certain aspects,the topical ocular formulation is a solution, a suspension or anemulsion. In another aspect, nintedanib is in an implant or semi-solidsustained release formulation injected into the affected eye. In certainaspects, the amount of nintedanib in the implant is from 1 μg to 100 mg.

In certain aspects, the disclosed methods are performed by thecombination of nintedanib and an antimetabolite drug. The antimetabolitedrug can be, but not limited to, Mitomycin C, 5-Fluorouracil,Floxuridine, Cytarabine, 6-Azauracil, Azathioprine, Methotrexate,Mycophenolate Mofetil, and Thiotepa.

In another aspect, the disclosed methods reduce scar formation inglaucoma surgery by attenuating abnormal vascularity and fibrosis at thesurgical site. In certain aspects, the disclosed methods are performedbefore operation, in conjunction with operation or after operation, toreduce failure in glaucoma surgery. Thus, in some aspects, the amount ofnintedanib administered is effective to reduce scar formation at thesite of the surgery. In some aspects, the amount nintedanib administeredis effective to extend the duration of lower IOP for at least 10 days,at least 365 days, or at least 3650 days following surgery. In someaspects, the amount of nintedanib administered is effective to prolongbleb survival

As used herein, the term “one or more” includes at least one, moresuitably, one, two, three, four, five, ten, twenty, fifty, one-hundred,five-hundred, etc., of the item to which “one or more” refers.

The term “subject” refers to an animal or human, or to one or more cellsderived from an animal or human. Preferably, the subject is a human.Subjects can also include non-human primates. A human subject can beknown as a patient.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description and figures, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a flow chart demonstrating an exemplary mechanism to reduceexcess scar formation and to improve the success rate of glaucomasurgery.

FIG. 2 is a graph showing bleb survival following glaucoma filtrationsurgery in a rabbit model.

FIG. 3 is a graph showing intraocular pressure (IOP) following glaucomafiltration surgery in a rabbit model.

FIG. 4 is a graph showing absolute success of glaucoma filtrationsurgery in a clinical study according to the methods disclosed herein.

DETAILED DESCRIPTION

Glaucoma is a group of diseases that are characterized by the death ofretinal ganglion cells (“RGCs”), specific visual field loss, and opticnerve atrophy. Glaucoma is a leading cause of blindness in the world. Avariety of treatment options, effective to reduce intraocular pressure(“IOP”), are available to control, and perhaps to slow, the progressionof the disease. Treatment options include, for example, pharmaceuticaltherapy (i.e., IOP-lowering drugs), laser eye surgery, and/orconventional surgical methods, such as glaucoma filtration surgery (oralso known as filtering surgery or trabeculectomy).

Despite the wide usage of topical IOP-lowering drugs in the developedcountries, glaucoma surgery is still commonly practiced in other partsof the world, especially for closed-angle glaucoma. Glaucoma surgery hasthe advantage of low cost over time and doesn't have to deal withcompliance issues associated with topical eye drops that need multipleapplications per day. The traditional glaucoma filtration surgery andtrabeculectomy have high failure rates (Schlunck et al. Exp Eye Res.2016; 142:76-82) and methods of implanting an ocular filtration device,e.g., a glaucoma drainage device, also have long term failure problems(Amoozgar et al. Curr Opin Ophthalmol. 2016; 27(2):164-9). The failuresare due to excessive postoperative wound healing with subsequentfibrosis and scar formation that obstruct drainage. The damage to tissueby surgery often induces pro-inflammation and pro-fibrogenic factorsthat lead to abnormal extracellular matrix change and fibrosis.Myofibroblast hyper-proliferation induced by these factors subsequentlycauses excessive fibrosis and scar formation.

The antimetabolite drug, mitomycin C (MMC) has been administered duringor after glaucoma surgery as an anti-scaring agent. Anotherantimetabolite drug, 5-fluorouracil (5-FU), is also used mainly by localinjection during follow-up (Schlunck et al. Exp Eye Res. 2016;142:76-82). These antimetabolite drugs work by blocking fastproliferating fibroblasts. Their activities are not selective and areknown to cause side effects. For example, the anti-cell divisionactivity sometimes causes bleb leakage post-surgery. Betterpostoperative management of glaucoma surgery is still an unmet medicalneed.

Due to the multi-factorial causes of scar formation following glaucomasurgery, targeting any single pathway alone may not be sufficient toimprove surgery success. The present disclosure improves glaucomasurgery success by administering to the eye a composition with thefollowing key attributes: 1) the composition will inhibit severalimportant pathological pathways simultaneously and these pathways aredisclosed below; 2) the composition utilizes small molecule drug(s) asopposed to antibody drugs to achieve a more efficient drug delivery tothe target tissue; 3) the composition is a topical formulation in theform of either an eye drop or implant for convenient and consistent drugdelivery to the site of surgery; and 4) the composition containsnintedanib, which can be used in combination with an antimetabolite drugto achieve an additive or synergistic effect in improving the success ofglaucoma filtration surgery.

The disclosure provides a method of using a topical formulation (e.g.,topical eye drop, implant) comprising nintedanib, before, during orafter surgery. Nintedanib meets the requirement of inhibiting vascularendothelial growth factor (“VEGF”) receptors (“VEGFR”) 1-3,platelet-derived growth factor receptor (“PDGFR”)-α and -β andfibroblast growth factor receptor 2 (“FGFR2”) to achieve the neededefficacy.

Without being bound to theory, it is understood that it is important toinhibit all VEGFR members because of the need to block placental growthfactor (“PIGF”) in addition to VEGF. PIGF only acts on pathologicangiogenesis and inflammation and contributes more to the problemsassociated with glaucoma surgery (Van Bergen et al. J Cell Mol Med.2013; 17(12):1632-43). For glaucoma filtration surgery, the disclosedmethods also inhibit FGFR2 due to its function in scar formation. Thetopical formulation disclosed herein allows for convenient treatmentbefore, during and after surgery. The mechanism for improving glaucomasurgery success rate provided by the present disclosure is summarized inFIG. 1, which shows that nintedanib, in a suitable ocular formulation,would simultaneously block signal pathways of the key pathogenic factorsinvolved in excess wound healing, including PIGF, VEGF, PDGF, FGF, andwould enhance the success of glaucoma surgery by reducing scarformation.

As used herein, the term “improving glaucoma surgery success” meansextending the duration of reduced (i.e., lower) IOP for a period of atleast 10 days, at least 90 days, at least 365 days, at least 750 days,or at least 3650 days following surgery, an increase of IOP-reductionpercentage comparing the pre-surgical baseline over a given period oftime (e.g., at least 10 days, at least 90 days, at least 365 days, atleast 750 days, or at least 3650 days) after surgery, increase of theabsolute (also known as complete) success rate (defined as percent ofpatients kept within normal IOP range with reduced IOP in relation tothe baseline without any glaucoma medication) over a given period oftime, increase of qualified success rate (defined as percent of patientskept within normal IOP range with reduced IOP in relation to thebaseline with the help of glaucoma medications) over a certain period oftime (e.g., at least 10 days, at least 90 days, at least 365 days, atleast 750 days, or at least 3650 days), improvement of the bleb gradeand survival over a certain period of time (e.g., at least 10 days, atleast 90 days, at least 365 days, at least 750 days, or at least 3650days).

As used herein, “normal IOP” or “normal IOP range” refers to intraocularpressure in the human eye of between about 5 mm Hg to about 22 mm Hg, orabout 10 mm Hg to about 21 mm Hg.

The terms “treatment”, “treating”, “treat” and the like are used hereinto generally refer to obtaining a desired pharmacologic and/orphysiologic effect. The effect can be prophylactic in terms ofcompletely or partially preventing a disease or symptom(s) thereofand/or may be therapeutic in terms of a partial or completestabilization or cure for a disease and/or adverse effect attributableto the disease. The term “treatment” encompasses any treatment of adisease in a mammal, particularly a human, and includes: (a) preventingthe disease and/or symptom(s) from occurring in a subject who may bepredisposed to the disease or symptom but has not yet been diagnosed ashaving it; (b) inhibiting the disease and/or symptom(s), i.e., arrestingtheir development; or (c) relieving the disease symptom(s), i.e.,causing regression of the disease and/or symptom(s). Those in need oftreatment include those already inflicted (e.g., those with high IOP,those with an infection, etc.) as well as those in which prevention isdesired (e.g., those with increased susceptibility to glaucoma, thosesuspected of having high IOP, etc.).

Nintedanib {Methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl) acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate} is akinase inhibitor as described herein. Nintedanib inhibits primarilyreceptor tyrosine kinases including, for example vascular endothelialgrowth factor receptor (VEGFR 1-3), platelet-derived growth factorreceptor (PDGFR α and β), fibroblast growth factor receptor (FGFR 1-4).

Formulations and Dosing Regimen

The methods described herein include the manufacture and use ofpharmaceutical compositions, which include compounds identified by amethod described herein as active ingredients. Also included are thepharmaceutical compositions themselves.

Pharmaceutical compositions typically include pharmaceuticallyacceptable excipients. As used herein the language “pharmaceuticallyacceptable excipient” or “pharmaceutically acceptable carrier” includessaline, solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration.

The phrase “pharmaceutically acceptable salt” as used herein means thosesalts of a compound of interest that are safe and effective foradministration to a mammal and that possess the desired biologicalactivity. Pharmaceutically acceptable acid salts include, but are notlimited to hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, isonicotinate, carbonate,bicarbonate, acetate, lactate, salicylate, citrate, tartrate,propionate, butyrate, pyruvate, oxalate, malonate, pantothenate,bitartarte, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, thanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., I,I′ methylene-bis-(2-hydroxy-3-naphthoate)) salts.Suitable base salts include, but are not limited to, aluminum, calcium,lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolaminesalts.

Methods of formulating suitable pharmaceutical compositions are known inthe art, see, e.g., Remington: The Science and Practice of Pharmacy,21st ed., 2005; and the books in the series Drugs and the PharmaceuticalSciences: a Series of Textbooks and Monographs (Dekker, N.Y.). Forexample, solutions, suspensions, creams, ointments, gels, gel-formingliquid, suspension containing liposomes or micelles, spray orformulation, or emulsions used for ophthalmic application can includethe following components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerin, propyleneglycol or other synthetic solvents; antibacterial agents; antioxidants;chelating agents; buffers such as acetates, citrates or phosphates andagents for the adjustment of tonicity such as sodium chloride ordextrose. The pH can be adjusted with acids or bases, such ashydrochloric acid or sodium hydroxide.

Pharmaceutical compositions suitable for injectable use can includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersion. It should be stable under the conditions ofmanufacture and storage and must be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (for example, glycerol, propylene glycol, and liquidpolyetheylene glycol, and the like), and suitable mixtures thereof. Theproper fluidity can be maintained, for example, by the use of a coatingsuch as lecithin, by the maintenance of the required particle size inthe case of dispersion and by the use of surfactants. Prevention of theaction of microorganisms can be achieved by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol,ascorbic acid, thimerosal, and the like. In many cases, it will bepreferable to include isotonic agents, for example, sugars, polyalcoholssuch as mannitol, sorbitol, and sodium chloride in the composition.Prolonged absorption of the injectable compositions can be brought aboutby including in the composition an agent that delays absorption, forexample, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle, which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze-drying, which yield a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

In one embodiment, the therapeutic compounds are prepared with carriersthat will protect the therapeutic compounds against rapid eliminationfrom the body, such as a controlled release formulation, includingimplants and microencapsulated delivery systems. Biodegradable,biocompatible polymers can be used, such as ethylene vinyl acetate,polyanhydrides, polyglycolic acid, collagen, polyorthoesters, andpolylactic acid. Such formulations can be prepared using standardtechniques, or obtained commercially.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

Compositions and formulations of nintedanib, can be administeredtopically (e.g., as a topical ocular formulation) or as an injection ofsemi-solid formulation or solid implant, or by any other suitablemethods known in the art. While it is possible to use the agentdisclosed herein for therapy as is, it may be preferable to administerthe agent as a pharmaceutical formulation, e.g., in admixture with asuitable pharmaceutical excipient, diluent, or carrier selected withregard to the intended route of administration and standardpharmaceutical practice. Pharmaceutical formulations include at leastone active compound, in association with a pharmaceutically acceptableexcipient, diluent, and/or carrier.

The pharmaceutical composition disclosed herein may include a“therapeutically effective amount” of an agent described herein. Sucheffective amounts can be determined based on the effect of theadministered agent, or the combinatorial effect of agents if more thanone agent is used. A therapeutically effective amount of an agent mayalso vary according to factors such as the disease state, age, sex, andweight of the individual, and the ability of the compound to elicit adesired response in the individual, e.g., amelioration of at least onedisorder parameter or amelioration of at least one symptom of thedisorder. A therapeutically effective amount is also one in which anytoxic or detrimental effects of the composition are outweighed by thetherapeutically beneficial effects.

Effective doses of the compositions of the present disclosure, for thetreatment of conditions vary depending upon many different factors,including means of administration, target site, physiological state ofthe subject, whether the subject is human or an animal, othermedications administered, and whether treatment is prophylactic ortherapeutic. Treatment dosages can be titrated using routine methodsknown to those of skill in the art to optimize safety and efficacy.

In some instances, the topical ocular formulation is a solution, asuspension, creams, ointments, gels, gel-forming liquid, suspensioncontaining liposomes or micelles, spray formulation, or an emulsion. Insome cases, the topical ocular formulation also includes one or morepharmaceutically acceptable excipients selected from stabilizers,surfactants, polymer base carriers, gelling agents, organic co-solvents,pH active components, osmotic active components and with or withoutpreservatives. In some cases, the sustained release semi-solidformulation, sustained release solid formulation or ocular implant isinjected into the affected eye. In some embodiments, the sustainedrelease semi-solid formulation, sustained release solid formulation orocular implant further comprises a pharmaceutically acceptableexcipient. In some cases, the sustained release semi-solid formulation,sustained release solid formulation or ocular implant includes amultikinase inhibitor, the antimetabolite, or combination thereof; and abiodegradable polymer selected from polylactic acid (PLA), polyglycolicacid (PLGA) and polylactic acid and polyglycolic acid copolymers.

Administration of a composition or formulation can be once a day, twicea day, three times a day, four times a day or more often. Frequency maybe decreased during a treatment maintenance phase of the treatment,e.g., once every second or third day instead of every day or twice aday. The dose and the administration frequency can be adjusted based onthe judgment of the treating physician, for example, taking into accountthe clinical signs, pathological signs and clinical and subclinicalsymptoms of a disease of the conditions treated with the presentmethods, as well as the patient's clinical history.

It will be appreciated that the amount of an agent disclosed hereinrequired for use in treatment will vary with the route ofadministration, the nature of the condition for which treatment isrequired, and the age, body weight and condition of the patient, andwill be ultimately at the discretion of the attendant physician.Compositions will typically contain an effective amount of nintedanib.Preliminary doses can be determined according to animal tests, and thescaling of dosages for human administration can be performed accordingto art-accepted practices.

Length of treatment, i.e., number of days, will be readily determined bya physician treating the subject; however, the number of days oftreatment may range from about 1 day to about 365 days. As provided bythe present methods, the efficacy of treatment can be monitored duringthe course of treatment to determine whether the treatment has beensuccessful, or whether additional (or modified) treatment is necessary.

Dosage, toxicity and therapeutic efficacy of the therapeutic compoundscan be determined by standard pharmaceutical procedures in cell culturesor experimental animals, e.g., for determining the LD50 (the dose lethalto 50% of the population) and the ED50 (the dose therapeuticallyeffective in 50% of the population). Dosage forms for nintedanib can bereadily determined by the ordinarily skilled artisan, and can e.g., beobtained in animal models and in clinical studies reported in theliteratures, for determining dosage, safety and efficacy according tostandard methods known in the art. The exact formulation, route ofadministration and dosage can be chosen by the individual physician inview of the patient's condition.

Compositions for use in the present methods may include nintedanib at aconcentration of 0.001% to 10% by weight or by volume the total amountof composition. For example, an aqueous composition comprises 0.001%,0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or up to 10% nintedanib.

As will be familiar to those skilled in the art, administration to theeye of an aqueous solution may be in the form of a “drop” or number ofdrops (e.g. of nintedanib solution) from a dropper or pipette or otherdedicated sterile devices. Such drops will typically be up to 50microliters in volume, but may be smaller e.g. less than 10 microliters.

EXAMPLES

The invention is further described in the following examples, which donot limit the scope of the invention described in the claims.

Example 1: Rabbit Glaucoma Surgery Model

The rabbit glaucoma surgery model is used to illustrate use of thepresently disclosed methods for improving the success of glaucomafiltration surgery. Specifically, an established rabbit model ofglaucoma filtration surgery would be used to study the effects ofnintedanib 0.2% solution on the wound-healing events after surgery. Thesurgical procedure is as described in Wong et al. (Wong et al. InvestOphthalmol Vis Sci. 2003; 44(3):1097-1103). Briefly, a partial thickness8-0 silk corneal traction suture is placed superiorly, and the eyepulled down. A fornix based conjunctival flap is raised, after which ablunt dissection of the subconjunctival space is performed ofapproximately 5 mm along the limbus and 8 mm posteriorly. Amicrovitreoretinal (MVR) blade is used to make a partial-thicknessscleral incision 3 to 4 mm behind the limbus, and a scleral tunnel tothe corneal stroma is fashioned. A 22-gauge, 25-mm intravenous cannula(Venflon 2; Beckton Dickinson, Oxford, UK) is passed through a scleraltunnel anteriorly until the cannula needle is visible in the clearcornea. Entry into the anterior chamber is made with a cannular needle,which is then withdrawn as the cannula is advanced to the mid-pupillaryarea. The cannula is trimmed and beveled at its scleral end so that itprotrudes 1 mm from the insertion point, and a 10-0 nylon suture isplaced to fix the tube to the scleral surface. The conjunctival incisionis closed with two interrupted sutures and a central, mattress-type 10-0nylon suture attached to a needle (B/V 100-4; Ethicon) to give awater-tight closure. One drop each of guttae chloramphenicol andBetnesol-N (Glaxo Wellcome, Uxbridge, UK) ointment is instilled at theend of surgery.

Twenty female New Zealand White rabbits (2-2.4 kg, 12-14 weeks old;Charles River) would be acclimatized for 5 days before the experimentsstart. Glaucoma surgery would be performed on the left eye as described.After surgery, the rabbits would be arranged into two groups and onegroup would be treated with vehicle and another with nintedanib 0.2%solution. Treatments would begin immediately after surgery and thetreatment would be TID for 2 weeks. The survival of the bleb formed bythe surgery and the intraocular pressure (IOP) would be followed for 28days. Histological analysis of the scar tissue would be performed at theend of the study.

Results

Surgery success outcome would be significantly prolonged in thenintedanib group compared with the vehicle group. FIG. 2 provides agraph showing the survival curve of the bleb after surgery. As shown inFIG. 2, the nintedanib group would show a substantially prolonged blebsurvival comparing to the vehicle group. By the end of study on day 28,no bleb would survive in the vehicle group while most of the bleb wouldsurvive in the nintedanib group. FIG. 3 is a graph showing the IOP curveduring the follow up period after the surgery. IOP remained low (i.e.,below 20 mm in the nintedanib group and increased gradually in thevehicle group. The difference would be statistically significant. Inaddition to bleb survival and IOP change, histological analysis of scartissue at the surgical site would show less scar tissue in thenintedanib group than the vehicle group.

The results from this experiment would indicate that the nintedanib 0.2%solution increases the success of glaucoma surgery (i.e., prolonged blebsurvival, extended duration of lower IOP following surgery and/orreduced fibrosis/scarring).

Example 2: Topical Ocular Formulations of Nintedanib as Adjunct Therapyto Glaucoma Filtration Surgery

Topical nintedanib 0.2% as adjunct therapy to increase success oftrabeculectomy in a clinical study. A randomized, double-masked,placebo-controlled, 12-month experimental trial to test the effects oftopical nintedanib 0.2% on the success rate of trabeculectomy. The studydesign would be as described by Vandewalle et. al. (Vandewalle et. al.Br J Ophthalmol. 2014, January; 98(1):73-8).

Patients with medically uncontrolled open-angle glaucoma scheduled for aprimary trabeculectomy would be enrolled and randomized to receive onedrop TID of either nintedanib or placebo solutions. The treatment wouldstart immediately after surgery and would last for a month.Approximately 150 patients would be enrolled in the study.

Surgeries would be performed under general or retrobulbar anaesthesia byexperienced surgeons using a modified Moorfields technique. IOP would bemeasured by Goldmann applanation tonometry. Two measurements would betaken by masked observers and averaged to determine the mean IOP if twovalues were within 2 mm Hg. A third measurement would be taken if thedifference between the first two determinations is >2 mm Hg.

Patients would be examined on day 1; at weeks 1, 2, and 4; and at months3, 6, and 12 after trabeculectomy. All patients would go through acomprehensive ophthalmic examination that included measurements ofbest-corrected visual acuity, slit-lamp examination, including, a Seideltest, IOP measurement, and fundus biomicroscopy with a 90-diopter lens.The number of postoperative IOP-lowering medications, intra- andpostoperative complications, and surgical interventions would also berecorded.

Absolute success would be the primary endpoint and would be defined asintraocular pressure (IOP)≤21 mm Hg and >5 mm Hg with at least 20%reduction from baseline and no loss of light perception.

Results

IOP would be effectively reduced in both nintedanib and placebo groupsat the 12-month visit when compared to baseline. The absolute successrate of glaucoma surgery, i.e., maintaining IOP of less than about 20 mmHg for more than 12 months after surgery, would be higher in thenintedanib group vs the placebo group as shown in FIG. 4. At time pointsafter 6 months, the differences would be statistically significant.

Example 3: Formulations

Nintedanib Ophthalmic Solution

The drug product is an isotonic ophthalmic solution prepared in2-hydroxypropyl beta cyclodextrin or other similar cyclodextrins, andbuffer solution, pH range from 5.5 to 8.0. Other viscosity, lubricant,preservative agents might be added to enhance functionality of theformulation. The compositions of the ophthalmic solution are disclosedin Table 1.

TABLE 1 Nintedanib Ophthalmic Solution Concen- tration Range IngredientsFunctions (% w/v) CBT-001 (Nintedanib free Active Pharmaceutical0.001-10   base) Ingredient Sodium Viscosity Agent/dry eye 0-1carboxymethylcellulose relief Pemulen TR Viscosity Agent  0-0.2Polyvinyl alcohol Viscosity/Lubrication  0-1.5 Agent HypromelloseLubricant/dry eye relief 0-1 Carbomers Lubricant/dry eye relief  0-0.5Carmellose sodium Lubricant/dry eye relief 0-1 Sodium hyaluronateLubricant/dry eye relief  0-1.5 Polyethylene glycol 400 Lubricant/dryeye relief  0-0.4 Propylene glycol Lubricant/dry eye relief  0-0.62-hydroxypropyl beta Solubilizer  0-10 cyclodextrin Sulfobutyl-beta-Solubilizer  0-10 cyclodextrin Randomly methylated beta- Solubilizer 0-5cyclodextrin α-cyclodextrin Solubilizer 0-4 β-cyclodextrin Solubilizer0-1 γ-cyclodextrin Solubilizer 0-1 Poloxamer 188, or 237, orSolubilizer/lubricant 0-5 407 Polysorbate 80 Solubilizer/lubricant/ 0-1surfactant Edetate disodium Chelating Agent/   0-0.01 PreservativeBenzalkonium chloride Preservative   0-0.02 Sodium phosphate BufferAgent   0-0.43 monobasic monohydrate Sodium phosphate dibasic BufferAgent  0-0.8 heptahydrate Boric acid Buffer Agent  0-0.6 Sodium borate,decahydrate Buffer Agent    0-0.045 Citric acid, monohydrate BufferAgent/preservative   0-0.13 Sodium citrate, dihydrate BufferAgent/preservative   0-0.45 Glycerin Tonicity Agent  0-2.2 Sodiumchloride Tonicity Agent   0-0.83 1N Sodium hydroxide pH Adjustment pH5.5-8.0 1N Hydrochloric acid Water for injection Vehicle Q.S. to 100Nintedanib Ophthalmic Suspension

The drug product is an isotonic ophthalmic suspension prepared incarboxymethylcellulose sodium and buffer solution, pH range from 5.5 to8.0. The drug particle sizes are reduced to below 40 micron. Otherviscosity, lubricant, solubilizer, and preservative agents might beadded to enhance functionality of the formulation suspension. Thecompositions are disclosed in Table 2.

TABLE 2 Nintedanib Ophthalmic Suspension Concen- tration RangeIngredients Functions (% w/v) CBT-001 (Nintedanib free ActivePharmaceutical 0.001-10   base) Ingredient Sodium Viscosity Agent/dryeye 0-1 carboxymethylcellulose relief Pemulen TR Viscosity Agent  0-0.2Polyvinyl alcohol Viscosity/Lubrication  0-1.5 Agent HypromelloseLubricant/dry eye relief 0-1 Carbomers Lubricant/dry eye relief  0-0.5Carmellose sodium Lubricant/dry eye relief 0-1 Sodium hyaluronateLubricant/dry eye relief  0-1.5 Polyethylene glycol 400 Lubricant/dryeye relief  0-0.4 Propylene glycol Lubricant/dry eye relief  0-0.62-hydroxypropyl beta Solubilizer  0-10 cyclodextrin Sulfobutyl-beta-Solubilizer  0-10 cyclodextrin Randomly methylated beta- Solubilizer 0-5cyclodextrin α-cyclodextrin Solubilizer 0-4 β-cyclodextrin Solubilizer0-1 γ-cyclodextrin Solubilizer 0-1 Poloxamer 188, or 237, orSolubilizer/lubricant 0-5 407 Polysorbate 80 Solubilizer/lubricant/ 0-1surfactant Edetate disodium Chelating Agent/   0-0.01 PreservativeBenzalkonium chloride Preservative   0-0.02 Sodium phosphate BufferAgent   0-0.43 monobasic monohydrate Sodium phosphate dibasic BufferAgent  0-0.8 heptahydrate Boric acid Buffer Agent  0-0.6 Sodium borate,decahydrate Buffer Agent    0-0.045 Citric acid, monohydrate BufferAgent/preservative   0-0.13 Sodium citrate, dihydrate BufferAgent/preservative   0-0.45 Glycerin Tonicity Agent  0-2.2 Sodiumchloride Tonicity Agent   0-0.83 1N Sodium hydroxide pH Adjustment pH5.5-8.0 1N Hydrochloric acid Water for injection Vehicle Q.S. to 100Nintedanib Ophthalmic Emulsion

The drug product is an isotonic ophthalmic emulsion. The drug isdissolved in the mixture oil phase and emulsifier excipients which isthen emulsified and mixed with an aqueous phase with pH range from 5.5to 8.0. Other viscosity, lubricant, solubilizer, and preservative agentsmight be added to enhance functionality of the emulsion formulation. Thecompositions are disclosed in Table 3.

TABLE 3 Nintedanib Ophthalmic Emulsion Concen- tration IngredientsFunctions (% w/w) CBT-001 (Nintedanib free Active Pharmaceutical0.001-10   base) Ingredient Castor oil Oil solvent   0-1.25Polyoxyl-40-Stearate Emulsifier   0-0.25 Polysorbate 80Solubilizer/Emulsifier/ 0-1 Surfactant Sulfobutyl-β-cyclodextrinSolubilizer 0-5 2-Hydroxypropyl-beta- Solubilizer 0-5 cyclodextrinRandomly methylated beta- Solubilizer 0-5 cyclodextrin α-cyclodextrinSolubilizer 0-4 β-cyclodextrin Solubilizer 0-1 γ-cyclodextrinSolubilizer 0-1 Glycerin Tonicity Agent  0-2.2 Sodium Chloride TonicityAgent   0-0.83 Pemulen TR2 Viscosity Agent  0-0.1 Sodium Viscosity Agent 0-0.5 carboxymethylcellulose Polyvinyl alcohol Viscosity/Lubrication 0-1.5 Agent Hypromellose Lubricant/dry eye relief 0-1 CarbomersLubricant/dry eye relief  0-0.5 Carmellose sodium Lubricant/dry eyerelief 0-1 Sodium hyaluronate Lubricant/dry eye relief  0-1.5Polyethylene glycol 400 Lubricant/dry eye relief  0-0.4 Propylene glycolLubricant/dry eye relief  0-0.6 Poloxamer 188, or 237, orSolubilizer/lubricant 0-5 407 Boric acid Buffer  0-0.6 Sodium borate,decahydrate Buffer    0-0.045 Citric acid, monohydrateBuffer/preservative   0-0.13 Sodium citrate, dihydrateBuffer/preservative   0-0.45 Sodium phosphate, Buffer   0-0.43 monobasicmonohydrate Sodium phosphate dibasic Buffer  0-0.8 heptahydrate 1N & 5NSodium pH Adjustment pH 5.5-8.0 hydroxide 1N Hydrochloric acid Water forinjection Aqueous Vehicle Q.S. 100Nintedanib Sustained Release Semi-Solid Formulation

The drug product is an isotonic sustained release semi-solidformulation. The drug is dissolved and/or suspended in a semi-solidmedium with pH range from 5.5 to 8.0. Other viscosity, lubricant,solubilizer, and preservative agents might be added to enhancefunctionality of the sustained release semi-solid formulation. Thecompositions are disclosed in Table 4.

TABLE 4 Sustained Release Semi-Solid Formulation Concen- trationIngredients Functions (% w/w) CBT-001 (Nintedanib free ActivePharmaceutical 0.001-10     base) Ingredient Xanthan GumViscosity/Thickener 0-10  Hydroxypropyl Viscosity/Thickener 0-10 methylcellulose Sodium hyaluronate Viscosity/Thickener 0-5   Hyaluronicacid Viscosity/Thickener 0-5   Boric acid Buffer 0-0.6  Sodium borate,decahydrate Buffer  0-0.045 Citric acid, monohydrate Buffer/preservative0-0.13 Sodium citrate, dihydrate Buffer/preservative 0-0.45 Sodiumphosphate, Buffer 0-0.43 monobasic monohydrate Sodium phosphate dibasicBuffer 0-0.8  heptahydrate 1N & 5N Sodium pH Adjustment pH 5.5-8.0hydroxide 1N Hydrochloric acid Water for injection Aqueous Vehicle Q.S.100Nintedanib Sustained Release Implants

The drug product is a solid implant. The drug is mixed and blended withone or more polymers. The mixture of drug and polymers is melted at apredetermined temperature and extruded into a filament with apredetermined diameter size. The formulation filament is cut into apredetermined size of segment which can be implanted into oculartissues. The compositions are disclosed in Table 5.

TABLE 5 Sustained Release Implants Concen- tration Ingredients Functions(% w/w) CBT-001 (Nintedanib free Active Pharmaceutical 0.001-10    base)Ingredient Poly (D,L-Lactide), i.v. Polymer 0-100 0.25-0.35 dL/g Poly(D,L-Lactide- Polymer 0-100 coglycolide) i.v. 0.14-0.22 dL/g Poly(D,L-Lactide), i.v. Polymer 0-100 0.16-0.25 dL/g Polyethylene Glycol3350 Polymer 0-20  Resomer ®RG755S Polymer 0-100 Resomer ®RG753H Polymer0-100

Without limitation, an example composition, for use in the methodsaccording to the invention, may be modified from existing ophthalmicallyacceptable compositions.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A method for improving success rate of glaucoma surgery, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1, wherein the nintedanib is administered in the form of topical eye drop or implant.
 3. The method of claim 1, wherein the amount of nintedanib administered is effective to reduce scar formation or reduce fibrosis at a site of the surgery in the eye of the subject.
 4. The method of claim 1, wherein the amount of nintedanib administered is effective to extend the duration of lower intraocular pressure (IOP), increase either the absolute success rate or the qualified success rate for at least 10 days following glaucoma surgery; or wherein the amount of nintedanib administered is effective to prolong bleb survival.
 5. The method of claim 1, wherein the nintedanib is administered in a form selected from the group consisting of a semi-solid or solid sustained-release implant injected into the eye of the subject.
 6. The method of claim 1, wherein the nintedanib is administered as a topical ocular formulation selected from the group consisting of a solution, suspension, or emulsion.
 7. The method of claim 1, wherein the administration is performed before, during or after glaucoma surgery.
 8. The method of claim 1, wherein the glaucoma surgery is performed using classic trabeculectomy or a method selected from the group consisting of Trabectome, gonioscopy-assisted transluminal trabeculotomy, excimer laser trabeculostomy, and endoscopic cyclophotocoagulation.
 9. The method of claim 1, wherein the glaucoma surgery performed is, for implanting an ocular filtration device.
 10. The method of claim 9, wherein the ocular filtration device is an ocular stent.
 11. The method of claim 1, wherein nintedanib is administered in combination with a cell-proliferation-inhibiting antimetabolite drug.
 12. The method of claim 11, wherein the antimetabolite drug is selected from the group consisting of mitomycin C, 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, azathioprine, methotrexate, mycophenolate mofetil, and thiotepa.
 13. A method of adjunctive treatment associated with glaucoma surgery in a subject, the method comprising administering to a subject in need thereof an effective amount of a composition comprising nintedanib or a pharmaceutically acceptable salt thereof.
 14. The method of claim 13, wherein the composition is administered in the form of topical eye drop or implant.
 15. The method of claim 13, wherein the composition contains an amount of nintedanib effective to reduce scar formation or reduce fibrosis at a site of the surgery in the eye of the subject.
 16. The method of claim 13, wherein the composition contains an amount of nintedanib effective to extend the duration of lower IOP, or increase either the absolute or the qualified success rate defined above, for at least 10 days following glaucoma surgery; or wherein the amount of nintedanib administered is effective to prolong bleb survival.
 17. The method of claim 13, wherein nintedanib administration is performed before, during or after glaucoma surgery.
 18. The method of claim 13, wherein nintedanib is in either a semi-solid or solid sustained-release implant is injected into the affected eye.
 19. The method of claim 13, wherein the nintedanib is administered as a topical ocular formulation selected from a group consisting of a solution, suspension or emulsion.
 20. The method of claim 13, wherein the glaucoma surgery is performed using classic trabeculectomy or a method selected from the group consisting of Trabectome, gonioscopy-assisted transluminal trabeculotomy, excimer laser trabeculostomy, and endoscopic cyclophotocoagulation.
 21. The method of claim 13, wherein the glaucoma surgery performed is, for implanting an ocular filtration device.
 22. The method of claim 21, wherein the ocular filtration device is an ocular stent.
 23. The method of claim 13, wherein nintedanib is administered in combination with a cell-proliferation-inhibiting antimetabolite drug.
 24. The method of claim 23, wherein the antimetabolite drug is selected from the group consisting of mitomycin C, 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, azathioprine, methotrexate, mycophenolate mofetil, and thiotepa.
 25. The method of claim 1, wherein the glaucoma surgery performed is a minimally invasive glaucoma surgery.
 26. The method of claim 13, wherein the glaucoma surgery performed is a minimally invasive glaucoma surgery.
 27. A method for improving success rate of implanting a stent in glaucoma surgery, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof. 